CMA increased detection rates and had a shorter turnaround time; therefore, late amniocentesis may serve as an extremely helpful tool for detecting abnormalities or reassuring parents following late appearing abnormal sonographic findings. However, CMA may expose uncertain findings for which the couple should be pre-counselled. The procedure appears safe. This article is protected by copyright. All rights reserved.

Whole exome sequencing (WES) is a powerful technique for identifying sequence changes in the human genome. The goal of this study was to delineate the genetic defects in patients with inherited retinal diseases (IRDs) using WES. WES was performed on 90 patient DNA samples from 68 families and 226 known genes for IRDs were analyzed. Sanger sequencing was used to validate potential pathogenic variants that were also subjected to segregation analysis in families. Thirty-three causative mutations (19 novel and 14 known) in 25 genes were identified in 33 of the 68 families. The vast majority of mutations (30 out of 33) have not been reported in the Israeli and the Palestinian populations. Nine out of the 33 mutations were detected in additional families from the same ethnic population, suggesting a founder effect. In two families, identified phenotypes were different from the previously reported clinical findings associated with the causative gene. This is the largest genetic analysis of IRDs in the Israeli and Palestinian populations to date. We also demonstrate that WES is a powerful tool for rapid analysis of known disease genes in large patient cohorts.

Purpose To identify the genetic cause and describe the phenotype in four families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. Design Case series. Subjects Seven patients from four unrelated families with arRP of which three patients had bilateral early-onset macular pseudocoloboma. Methods We performed homozygosity mapping and whole-exome sequencing (WES) in five probands and two unaffected family members of four unrelated families. Subsequently, Sanger sequencing and segregation analysis were done in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography (ffERG), fundus photography, fundus autofluorescence imaging and optical coherence tomography. Main Outcome Measures IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, ffERG, fundus autofluorescence and OCT findings. Results We identified seven different variants in IDH3A in four unrelated families, i.e. five missense, one nonsense and one frameshift variant. All subjects developed symptoms early in life ranging from night blindness to decreased visual acuity and were diagnosed between the ages of one and 11 years. Four subjects with biallelic IDH3A variants displayed a typical arRP phenotype and three subjects were diagnosed with arRP and pseudocoloboma of the macula. Conclusions IDH3A variants were identified as a novel cause of typical arRP, in some individuals associated with macular pseudocoloboma. We observed both phenotypes in two siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

A growing number of human diseases have been linked to defects in protein glycosylation that affects a wide range of organs. Among them, O-mannosylation is an unusual type of protein glycosylation that is largely restricted to the muscular and nerve system. Consistently, mutations in genes involved in the O-mannosylation pathway result in infantile-onset, severe developmental defects involving skeleton muscle, brain and eye, such as the muscle-eye-brain disease (MIM no. 253280). However, the functional importance of O-mannosylation in these tissues at later stages remains largely unknown. In our study, we have identified recessive mutations in POMGNT1, which encodes an essential component in O-mannosylation pathway, in three unrelated families with autosomal recessive retinitis pigmentosa (RP), but without extraocular involvement. Enzymatic assay of these mutant alleles demonstrate that they greatly reduce the POMGNT1 enzymatic activity and are likely to be hypomorphic. Immunohistochemistry shows that POMGNT1 is specifically expressed in photoreceptor basal body. Taken together, our work identifies a novel disease-causing gene for RP and indicates that proper protein O-mannosylation is not only essential for early organ development, but also important for maintaining survival and function of the highly specialized retinal cells at later stages.

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